Peripheral arterial disease affects millions of people and is the major reason for amputations in this country. Therapeutic angiogenesis has been explored as a plausible treatment for a number of years, but with only limited success, highlighting the need for a better understanding of how angiogenesis is triggered and regulated during ischemia. PGC-1alpha is a transcriptional coactivator that controls genes important for mitochondrial function and energy homeostasis in highly metabolic organs such as the skeletal muscle, heart and liver. Recent studies in our lab resulted in the discovery of a novel and powerful angiogenesis pathway, in which PGC-1alpha regulates various angiogenic genes including VEGF. This pathway functions under hypoxic and nutrient deprived conditions and requires the coactivation of the orphan nuclear receptor ERRalpha. The specific aims of my research will be to study if PGC-1alpha can induce functional blood vessels in adult skeletal muscle and if this angiogenic pathway can protect against ischemic injury, especially limb ischemia. I will also investigate the transcription factors that associate with PGC-1alpha in regulating this pathway. Biochemical, cell culture, and in vivo models will be used, including mice genetically modified to induce PGC-1alpha in muscle, and a well-established murine model of hind- limb ischemia. My studies will help gain a thorough understanding of the angiogenic pathway and the role of PGC-1alpha in normal and ischemia induced angiogenesis. These experiments may also lead to new therapeutic approaches for ischemic conditions such as peripheral arterial disease. PUBLIC HEALTH RELEVANCE: The blockage of blood vessels in the limbs affects millions of people in the US and is the leading cause of amputations, and yet therapeutic interventions remain few and ineffective. We have discovered a new angiogenic pathway that involves the transcriptional coactivator PGC-11 in the skeletal muscle. I propose to investigate if this pathway can form functional blood vessels, protect against muscle damage from blocked blood vessels and henceforth provide a new therapeutic approach to this debilitating disease.